title: Mechanisms for increased insulin-stimulated Akt phosphorylation and glucose uptake in fast- and slow-twitch skeletal muscles of calorie-restricted rats.
abstract: Calorie restriction [CR; ~65% of ad libitum (AL) intake] improves insulin-stimulated glucose uptake (GU) and Akt phosphorylation in skeletal muscle. We aimed to elucidate the effects of CR on 1) processes that regulate Akt phosphorylation [insulin receptor (IR) tyrosine phosphorylation, IR substrate 1-phosphatidylinositol 3-kinase (IRS-PI3K) activity, and Akt binding to regulatory proteins (heat shock protein 90, Appl1, protein phosphatase 2A)]; 2) Akt substrate of 160-kDa (AS160) phosphorylation on key phosphorylation sites; and 3) atypical PKC (aPKC) activity. Isolated epitrochlearis (fast-twitch) and soleus (slow-twitch) muscles from AL or CR (6 mo duration) 9-mo-old male F344BN rats were incubated with 0, 1.2, or 30 nM insulin and 2-deoxy-[(3)H]glucose. Some CR effects were independent of insulin dose or muscle type: CR caused activation of Akt (Thr(308) and Ser(473)) and GU in both muscles at both insulin doses without CR effects on IRS1-PI3K, Akt-PP2A, or Akt-Appl1. Several muscle- and insulin dose-specific CR effects were revealed. Akt-HSP90 binding was increased in the epitrochlearis; AS160 phosphorylation (Ser(588) and Thr(642)) was greater for CR epitrochlearis at 1.2 nM insulin; and IR phosphorylation and aPKC activity were greater for CR in both muscles with 30 nM insulin. On the basis of these data, our working hypothesis for improved insulin-stimulated GU with CR is as follows: 1) elevated Akt phosphorylation is fundamental, regardless of muscle or insulin dose; 2) altered Akt binding to regulatory proteins (HSP90 and unidentified Akt partners) is involved in the effects of CR on Akt phosphorylation; 3) Akt effects on GU depend on muscle- and insulin dose-specific elevation in phosphorylation of Akt substrates, including, but not limited to, AS160; and 4) greater IR phosphorylation and aPKC activity may contribute at higher insulin doses.
authors.affiliation: Muscle Biology Laboratory, School of Kinesiology, Ann Arbor, MI 48109-2214, USA.
authors.forename: Naveen
authors.initials: N
authors.lastname: Sharma
authors.forename: Edward B
authors.initials: EB
authors.lastname: Arias
authors.forename: Abhijit D
authors.initials: AD
authors.lastname: Bhat
authors.forename: Donel A
authors.initials: DA
authors.lastname: Sequea
authors.forename: Steve
authors.initials: S
authors.lastname: Ho
authors.forename: Kelsey K
authors.initials: KK
authors.lastname: Croff
authors.forename: Mini P
authors.initials: MP
authors.lastname: Sajan
authors.forename: Robert V
authors.initials: RV
authors.lastname: Farese
authors.forename: Gregory D
authors.initials: GD
authors.lastname: Cartee
mesh_terms: D000263:Adenylate Kinase / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D001835:Body Weight / Q000502:physiology; D031204:Caloric Restriction; D003847:Deoxyglucose / Q000378:metabolism; D004435:Eating / Q000502:physiology; D005947:Glucose / Q000378:metabolism*; D051275:Glucose Transporter Type 4 / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D047468:Immunoprecipitation; D007328:Insulin / Q000494:pharmacology*; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism; D018656:Muscle Fibers, Fast-Twitch / Q000187:drug effects / Q000378:metabolism*; D018657:Muscle Fibers, Slow-Twitch / Q000187:drug effects / Q000378:metabolism*; D051058:Oncogene Protein v-akt / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011506:Proteins / Q000378:metabolism; D051381:Rats
chemical_list: D051275:Glucose Transporter Type 4; D007004:Hypoglycemic Agents; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; C526296:Irs1 protein, rat; D011506:Proteins; C495694:Slc2a4 protein, rat; C540572:TBC1D1 protein, rat; D003847:Deoxyglucose; D019869:Phosphatidylinositol 3-Kinases; D051058:Oncogene Protein v-akt; D000263:Adenylate Kinase; D005947:Glucose